5-acylimino-nu-alkyl-4-alkyl-delta2-1, 3, 4-thiadiazoline-2-sulfonamides



-ACYLl1VHNO-N-ALKYL-4-ALKYLA-1,3,4-THIADI- AZOLINE-2-SULFONAM1DES Rocco Joseph Lopresti, Brooklyn, N.Y.; Sidney Robert Safir, River Edge, NJ.; Richard William Young, Riverside, Conn.; and Charles Edward Rauh, Bogota, N.J., assignors to American Cyanamid Company, New York, N.Y., a corporation of Maine No Drawing. Filed Dec. 8, 1958, Ser. No. 778,619

8 Claims. (Cl. 260-3065) This invention relates to novel organic compounds and more particularly is concerned with novel 5-acylimino- N alkyl 4 alkyl A 1,3,4 thiadiazoline 2 sulfonamides which may be represented by the following general formula:

O Rr-N--'N R- --N=( 3 t z-soi-Nn-ai S wherein R is hydrogen or lower alkyl and R and R are lower alkyl. Suitable lower alkyl substituents are methyl; ethyl, propyl, isopropyl, butyl, amyl, hexyl, etc.

The compounds of this invention are useful pharmaceuticals. It has been discovered that these compounds possess desirable pharmacological properties and in particular are capable of producing pronounced anaesthesia of short duration upon intravenous administration in man and animals with minimal side eifects. The dosage required to produce surgical anaesthesia of from to 60 minutes duration without noticeable toxic side effects varies between 10 milligrams and 209 milligrams per kilogram of body weight.

The compounds are related to the heterocyclic sulfonamides described in the patent to Richard W. Young et al., No. 2,783,241, which are useful carbonic anhydrase inhibitors. The new compounds herein may be'considered to be alkyl derivatives of methazolamide described in this patent in that the sulfonamide radical of the parent compound is substituted by a lower alkyl group. Unexpectedly, however, this substitution produces a striking change in the activity of the resulting compounds. The new compounds unexpectedly produce a state of general anaesthesia. Methazolamide exhibits no anaesthetic properties even in large dosages when similarly administered.

The compounds may be prepared by reacting a S-acetylimino-4-alkyl-A -l,3,4-thiadiazoline-2-su1fonyl chloride with an appropriate amine in the presence of a suitable non-hydroxylated organic solvent such as benzene, toluene, etc. The reaction may be carried out at'temperatures ranging from about C. to about 40 C. The resulting 5 acetylimino N alkyl 4 alkyl- A 1,3,4-thiadiazobutyric acid, propionic acid, etc., at temperatures between about 70 C. to 115 C. so as to form the corresponding 5 acylimino N alkyl 4 alkyl 7 A 1,3,4 thiadiazoh'ne-Z-sulfonamide.

The above reaction is illustrated schematically below:

R2-N N c1130 0N=( 3 is0,cl+R|NH=- nited States Patent 0 wherein R, R and R are lower alkyl radicals.

Alternatively, the N alkyl 5 -imino-4-alkyl-A -1,3,4- thiadiazoline-Z-stflfonamide hydrochloride prepared as above-described may be treated with an excess of gaseous ammonia for a period from about 5 minutes to 1 hour to form the corresponding N-alkyl-S-iminoA-alkyl-M- l,3,4-thiadiazoline-2-sulfonamide. This product may then be reacted with formic acid in the presence of a lower alkanoic anhydride such as acetic anhydride, butyric anhydiide, etc. to form the corresponding 4-alkyl-5- formylimino N alkyl A 1,3,4-thiadiazoline-2-sulfonamide. This series of reactions may be illustrated by the following equation wherein R and R are lower alkyl radicals.

The invention will be described in greater detail in conjunction with the following specific examples.

EXAMPLE 1 Pr paration of S-acetylimino-N-sec. butyl-4-methyl A 1 ,3,4-th iadiazolin e-2-sulfonamide To a solution of 25.3 g. of sec. butylamine dissolved in 300 ml. of benzene there was added 44.4 g. of S-acetylimino-4-methyl-A -1,3,4-thiadiazoline-2-sulfony1 chloride.

Thetollowing compounds were prepared by reacting 5 'acetylimino-4-methyl-A -1,3,4-thiadiazoline-Z-sulfonyl chloride with the appropriate amine as described in- Example 1.

Example No. R1 R2 M.P., 0,

CH5- CH3- 163-164. 5 CHsCHP 0113-- 154-155 CHQOHQCHZ" CH3- 143-144 (GH3)2 H CH3- 200-201. 5 CH3CH2CH:CH: CH3- 1-15. 5-146. 5 (CH3); CH-r 173-174 CH1= G(.CH3) CH: CH3 137-138 GHa(CH2)aCH2 CH3- 106-109 (OH3);CHCH:CH2- CH: 127-130 CH:(CH2)4CH2 CH3 121 (CHzOzCHCHr CHs 136. 5l37. 5

EXAMPLE 13 Preparation of N-propyl-S-imin0-4-methyl-A -l,3,4-thiadiazoline-Z-sulfonamide hydrochloride A solution of 24.1 g. of 5 acetylim-ino-4-methyl-N- propy1-A -1,3,4-thiadiazoline-2-sulfonamide in 439 cc. of dry ethanol and 44 cc. of 12 N hydrochloric acid was refiuxed for 1% hours. Upon cooling in ice, a colorless solid crystallized and was filtered; M.P. 203207 (dec.).

Patented June 14, 1960' .heated for 1% hours at 1-10-115 cooled in an ice bath and then diluted withpetroleum- 3 EXAMPLE 14 Preparation of N-tert. butyl-5-imino-4-methyl-A -l,3,4-

' thiadiazoline-Z-sulfofiizmide hydrochloride The procedure of the preceding example was repeated except that an equivalent quantity of 5-acetylimino-4- methyl-N-tert. butyl-A -1,3,4-thiadiazoline-Z-srflfonamide was used. N-tert. butyl-S-imino-4-methyl-A -1,3,4-thiadiazoline-Z-sulfonamide hydrochloride having a melting point of 215-219" (dec.) was obtained.

7 7 EXAMPLE Preparation of N-sec. butyl-S-imfno 4-nithy1 A'=I,3,4- thiadiazoline-Z-SuIfonamide hydrochloride The procedure of Example 13 was repeated except tha -t an equivalent quantity of 5-acetylimino-4-methyl-N-sec. butyl-A' 1,3,4-thiadiaZoline-2-sulfonamide was used. N- sec. butyl-S-imino-A-methyl-N-l,3,4-thiadiazoline-2-sulfonamide hydrochloride having a melting point'of 1'98- 201" (dec.) was obtained.

7 7 EXAMPLE 16 Preparation of N-isobutyl-5-imino-4-methyi-Ai1 ,3,4-thiddiazoline-Z-sulforidmide hydrochloride The procedure of Example 13 was repeated except that an equivalent quantity of 5-acetylimino-4-methyl-N- isobutyl-A -l,3,4-thiadiazoline-2-sulfonamide was used. N isobutyl 5 imino 4-- methyl- A 1,3,4 thiadiazoline-Z-sulfonarnide hydrochloride having a melting point of 211-214" (dec.) was'obtained EXAMPLE 17 Preparation of N-s'kc. butyl- -buryrylimino-4-methyl-A=- 1,3,4-thiadidZoIine-Z-sulfonomide A mixture of 8 g. of N-sec. buty1-5-imir1o-4-methyl- A34,3,4-thiadiazoline 2-sulfonamide hydrochloride} 17.7

r 4 vacuo to yield .a solid, which was suspended in 200 ml. of hot water. The mixture was filtered and the insoluble material was recrystallized from methanol to yield 5-acetylirnino-4-ethyl-N propyi A -1,3,4 thiadiazoline- 2-sulfonamide; M.P. 130-1315;

' EXAMPL-Ejj Preparation of 5 -acet ylimi rz' o;N-tgrzf. buryl-4-ethyl-Al I,3,4-thiadioioline-Z-sulfondrhide The procedure of'Exaihple 3?. was repeated except that an equivalent quantity of te'rt. bu'tylarnine was used.

2-sulfonamide having a melting point of 151.5-153" was obtained. EXAMPLE 34 Preparation of iV-proiiyl-d-cthyl-i-irhirio-d-i,id-ihiodiazolirm-Z-sizlfmamide hydrochloride .A' solution of 25.8 g. of 5-acetylimino-4ethyl-N- ropyl-A -1,3,4-thiadiazoline-Z-sulfonamide in 500 cc. of

dry ethanol and 50 cc. of 12 N hydrochloric acid was refluxed for 1 /1 hours. Upon cooling inice a colorless solid crystallized and was filtered; M. P. 167-169 (dec.).

g 7 EXAMPLE 3s Prparotio'ri of N-trtl bugle-anyMarti a-M13417;111- didzolihe-Zmulf'ondmid hydrochloride P1914 1"? Q51 li yfldins e an p a epeate except that j -acetylirnino-4;ethyl-N-tert. .butyl-A -1,3,4- thiadiazoline-2;sulfonamide was 7 used. N-tert... butyl-4- ethyl-5-imino-AF-1,3,4-thiadiazoline-2rsulfonamide hydro- 7 V chloride having a melting point of 143-l50 (de'c.) was g. Ofbutyric anhydride and 35 m1. of butyric acid was 1 The reaction was ether. The mixture was filtered and the insoluhle material was first washed with water and then recrystallized from 50% alcohol to give N-sec. butyl-5 bu'tyrylimino- 4-methyl'-A -1,3,-thiadiaioline-2-sulfonan1ide; MP. 112- 11 2.5. 7 V

' EXAMPLES: 18-31 The following: compounds were prepared 11y feaoting the appropriate 5-imino-N alkyl-4-methyl-A -1,3,4-thiadiazoline 2-sultonamide hydrochloride withthe appro- Preparation of 5-acetylimir 0-4-ethyl-N-propyl-M-IJA- thiadiazoline-Z-sulfonamide To a solution of 25.8 g. of propylamine and 750 ml.

of benzene, there was added in the cold 41.2 g; of-

5-acetylimino-4-ethyl-A -1,3,4 thiadiazoline 2 sulfonyl chloride. The reaction was permitted toi-stand at room temperature'for12 hours and'was thenconc'e'ntrated in:

obtained.

EXAMPLE 36 7 Preparation" of 4-eihyl-5-probioriylirrliuo'- N prowl-A 1,3,4-thiadiazoline-Z-sidfonamid A mixture pr- 2.9 g1 of 4ethyl:Sdmino-N-propyl-A? 1,3;4 thiadifioline-l-sulfonamide hydrochloride,- 5.3 g. of propionic anhydride and 15 m1. of propionic acid was heated at 1l( )-1l5 for 1 hours. The solution was cooled and then diluted with petroleum-ether. The resulting mixture was filtered and the insoluble material was first washed with water and then recrystallized from alcohol-petroleum ether to give 4-ethyl-5propionyliminov N propyl-A -1,3,4-thiadiazoline 2 sulfonamide; M.P. 83.5-".

EXAMPLE 37 Pr'epz'zratioh of 5 -11 zityrylimino-4-thyl-N-propyFA -1,3,4-

thiadiazolin-Z-sulfonahtide The procedureiof Example 36 was repeated using an equivalent quantity of butyric anhydrideaan'd butyric acid. The resulting 5-butyrylimino-4-ethyl-N-propyhA -1,3,4- thiadiazoline-Z-sulfonarhid'e had a melting" point of 84-85 C. i y

EXAMPLE" 38 of 4;cihyl-N-propy l-5 volerylimirio-h l3,4-

thiddiazolirie-2-sulfoizomide' The prbcedure'of- Example 36" was repeated'usingan equivalent quantity'of' valeric anhydride and'valei'ic acid. 4-eth'y1N -propyl 5' valerylimino=A -l,3L4-thiadia2oline- 2-sulfonair1idehavinga meltingpoint of'80-81 Cywas obtained. 7

Preparation AMI 1 1E" 39" Prirariziion ofN-ie i't." bdtyI-S-biItyryZiIriiiio {4 ethyl-A 1,3,4-thiadiazoline-2-sulfonamide I The procedure of Example 36 was repeated using an equivalent amount of butyric anhydride, butyric acid, and 4-ethyl 5 imino-N-tert. butyl A l;3,4-thiadiazoline-2- sulfonamide hydrochloride. a melting point of 119-120 C.

The resulting compound had I EXAMPLE 40 Preparation of N-tert. butyl-4-ethyI-S-iminO-A -I,3,4- thiadiazoline-Z-sulfonamide To a suspension or" N-tert. buty1-4-ethyl-5-imino-A l,3,4-thiadiazoline-Z-sulfonamide hydrochloride in 75 cc. of chloroform at 25, there was introduced an excess of gaseous ammonia. The mixture was filtered and the filtrate was evaporated to dryness in vacuo to yield a crude solid which was recrystallized from ethanol-petroleum ether to give a light yellow solid, Ml. 131-13? (deo).

EXAMPLE 41 Preparation of N-isobutyl 4 methyI-S-imirm-A -I,3,4- thiadiazoline-Z-sztlfonamide The procedure of Example 40 was repeated using N-iso'outyl-4-methyl 5 imino-A -1,3,4-thiadiazoline-2- sulfonamide hydrochloride. The resulting N-isobutyl-4- methyl-S-imino-M-l,3,4-thiadiazoline-2-su1f0namide had a melting point of 8792 C.

EXAMPLE 42 Preparation of N-propyl-4-ethyl-5-imin0-A -1,3,4-thiadiazoline-Z-sulfonamide The procedure of Example 40 was repeated using N-propyl-4-ethyl 5 iminQ-A -I,3,4-thiadiazoline-2-sulfonamide hydrochloride. The resulting N-propyl-4-ethyl- S-iminQ'A -I,3,4-thiadiazoline 2 sulfonamide was obtained as a yellow oil.

EXAMPLE 43 Preparation of 4-ethyl-5-f0rmylimin0-N -prapyl-A -1 ,3,4- thiadiazoline-Z-sulfonamide A solution of 1 g. of 4-ethyl-S-imino-N-propyl-M-1,3,4- thiadiazoline-Z-sulfonamide, 6 ml. of formic acid 2.2 ml. of acetic anhydride was refluxed for 1% hours. The solution was poured into ice-water and crystallization took place. The mixture was filtered and the insoluble material was recrystallized from alcohol-petroleum ether to yield a product melting at 115-117" C.

EXAMPLE 44 Preparation of 4-ezhyl-5-f0rmylimino-N-tert. butyl-A l,3,4-thiadiazoline-Z-sulfonamia'e The procedure of Example 43 was repeated using 4-ethyl-5-imino-N-tert. buty1-A -1,3,4-thiad.iazoline 2-sulfonamide. The resulting 4-ethyl-5-formy1imino-N-tert.

butyl-N-l,3,4-thiadiazoline-2-sulfonamide had a melting point of 122124 C.

EXAMPLE 45 Preparation of 4-methyl-5-formylimino-N-isobutyl- A -l ,3,4-thiadiaz0line-2-sulfonamide The procedure of Example 43 was repeated using 4methyl-5-imino N isobutyl A 1,3,4 thiadiazoline- 2-su1fonamide. The resulting 4-methyl-5-formylimino-N- isobutyl-A -1,3,4-thiadiazoline-2-sulfonamide had a melting point of -112 C.

We claim:

1. 5-acylimino-N-alkyl-4-alkyl-A 1,3,4 thiadiazoline-Z- sulfonamides of the formula:

wherein R is selected from the group consisting of hydrogen and lower alkyl and R and R are lower alkyl radicals.

2. 5-propionylimino-N-propy1- 4 ethyl A -1,3,4 thiadiazoline-Z-sulfonamide.

3. S-acetylimino-N propyl-4 methyl A -1,3,4 thiadiazoline-Z-sulfonamide.

4. S-butyrylimino-N-sec. butyl-4-mcthyl-A -1,3,4-thiadiazoline-Z-sulfonamide.

5. 5-propionylimino-N-tert. butyl 4-ethy1-A -1,3,4-thiadiazoline-Z-sulfonamide.

6. 5 acetylimino-N-isopropylA-methyl-A 1,3,4-thiadiazoline-Z-sulfonamide.

7. 5-propionylimino-N-isobutyl-4 methy1-A=-1,3,4-thiadiazoline-Z-stflfonamide.

8. A method of preparing 5-acylimino-N-a1ky1-4-a1kyl- A -1,3,4-thiadiazoline-2-sulfonamides of the formula:

wherein R is selected from the group consisting of hydrogen and lower alkyl and R and R, are lower alkyl radicals which comprises reacting the corresponding 5-acylimino-N-alkyl-4-a1ky1-A -L3A thiadiazoline 2-su1- fonyl chloride with a lower alkyl amine.

References Cited in the file of this patent UNITED STATES PATENTS 2,783,239 Young et a1 Feb. 26, 1957 

1. 5-ACYLIMINO-N-ALKYL-4-ALKYL-$2-1,3,4-THIADIAZOLINE-2SULFONAMIDES OF THE FORMULA: 